Project Summary/Abstract In 2015, over 63% of drug overdose deaths involved an opioid of which nearly half involved a prescription opioid. While most opioid deaths and overdoses are likely due to illicitly-manufactured fentanyl, prescription opioid use for treatment of acute pain appears to be a gateway for development of opioid use disorders through prescribed or diverted use in patients or non-patients, respectively. Specifically, of the >70 million patients who receive prescription opioids for acute pain following minor or major surgery every year in the US, an estimated 6% go on to use opioids persistently. In 2016, 53% of individuals aged 12 years or older who reported non-medical use of prescription opioids obtained the misused/diverted medications from family or friends. Therefore, developing a non-opioid analgesic medication to manage acute, post-operative pain should reduce or replace opioid prescriptions and thereby prevent opioid use disorders. The voltage-gated sodium ion channel NaV1.7 is preferentially expressed in peripheral somatic and visceral sensory neurons within the dorsal root ganglion, including nociceptors, olfactory sensory neurons and sympathetic ganglion neurons. Global knockout of NaV1.7 in mice resulted in insensitivity to painful tactile, thermal and chemical stimuli and anosmia. A similar phenotype is observed in humans with congenital insensitivity to pain in whom loss-of-function mutations in NaV1.7 lead to an inability to experience most types of pain but have otherwise normal neuronal function except for loss of smell. In contrast, dominantly inherited gain- of function missense mutations of NaV1.7 are found in patients with erythromelalgia and paroxysmal extreme pain disorder, who report flushing and severe, episodic pain triggered by mild warmth or bowel movement. Based on these data, and the very low expression of NaV1.7 in the CNS, NaV1.7 inhibitors have the potential to decrease acute pain intensity without opioid-like addiction liability. At least five NaV1.7 inhibitors have been assessed in clinical trials, yet none has advanced beyond Phase 2. While this might be interpreted as evidence that inhibiting NaV1.7 is not sufficiently analgesic, attainment of clinically-meaningful levels of channel blockade is challenging. This is especially true with state-dependent inhibitors of NaV1.7 (PF-05089771, GDC-0276, GDC-0310), highly protein-bound drugs (PF-05089771), and drugs with low-to-moderate selectivity for NaV1.7 (XEN-402, CNV-1014802) where off-target interactions limit the dose that can be safely administered in clinic. ST-2427 is a novel, first-in-class, state-independent inhibitor of NaV1.7 with nonclinical data demonstrating its safety and acceptable pharmacokinetic properties, and its potential for superior efficacy to opioids. This proposal aims to complete IND-enabling research and conduct Phase 1 and Phase 2 clinical trials with ST-2427 for treatment of acute, post-operative pain, and an assessment of the potential to significantly reduce and/or eliminate opioid consumption.